ENCODE 3 (2012-2017) expanded production and added new types of assays 8 (Fig. 1, Extended Data Fig. 1), which revealed landscapes of RNA binding and the 3D organization of chromatin via methods such as chromatin interaction analysis by paired-end tagging (ChIA-PET) and Hi-C chromosome conformation capture. Phases 2 and 3 delivered 9,239 experiments (7,495 in human and 1,744 in mouse) in more than 500 cell types and tissues, including mapping of transcribed regions and transcript isoforms, regions of transcripts recognized by RNA-binding proteins, transcription factor binding regions, and regions that harbour specific histone modifications, open chromatin, and 3D chromatin interactions. The results of all of these experiments are available at the ENCODE portal (http://www.encodeproject.org). These efforts, combined with those of related projects and many other laboratories, have produced a greatly enhanced view of the human genome (Fig. 2), identifying 20,225 protein-coding and 37,595 noncoding genes

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The ENCODE project has produced a collection of RNA sequencing experiments from many cell lines and bulk tissues that constitutes an extensive catalogue of the expression programs utilized in the human body. However, the relationship between the transcriptomes of tissues and those of the constituent primary cells, and how these impact tissue phenotypes has not been well established. Here we have produced RNA sequencing data for a number of primary cells from ten human body locations. The analysis of this data, together with additional epigenetic data from a total of 146 primary cells, indicates that many cells in the human body belong to five major cell types of similar transcriptional complexity: three, epithelial, endothelial, and mesenchymal, are broadly distributed across the human body acting as components for many tissues and organs, and two, neural and blood cells, are more anatomically localized. Based on gene expression, these redefine the basic histological types by which tissues have been traditionally classified.We have identified genes whose expression is specific to these cell types, and have estimated the relative proportion of the major cell types in human tissues using the transcriptional profiles produced by the GTEx project. The inferred cellular composition is a characteristic signature of tissues and reflects tissue morphological heterogeneity and histology. We identified changes in cellular composition in different tissues associated with age and sex and found that departures from the normal cellular composition correlate with histological phenotypes associated to disease. This transcriptionally based classification of human cells provide a new view of human biology and disease.2 Transcriptional profiles reflect cell type, condition and function. In tissues and organs, they are monitored in RNA extracted from millions to billions of cells (11 6 − 10 9 ) 1 , likely including multiple cell types. As a consequence, the transcriptional profiles obtained from tissue samples represent the average expression of genes across heterogeneous cellular collections, and gene expression differences measured in bulk tissue transcriptomes may thus reflect changes in cellular composition rather than changes in the expression of genes in individual cells. Single-cell RNA sequencing (scRNA-seq) has indeed revealed large cellular heterogeneity in many tissues and organs 2 , and the Human Cell Atlas (HCA) project 3 has been recently initiated with the aim of defining all human cell types and to infer the cellular taxonomy of the human body.As a step in that direction and to bridge the transcriptomes of tissues with the transcriptomes of the constituent primary cells, and to understand how these impact tissue phenotypes, we have generated bulk expression profiles of 53 primary cell lines isolated from ten different anatomical sites in the human body.These profiles include long and short strand-specific RNA-seq, and RAMPAGE data (Fig. 1a, Table S1-4). Major cell types in the human bodyClustering of the primary cell...

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